ST2L (IL1RL1, DER4, T1, FIT-1) is a member of the Toll-like/IL-1 receptor superfamily. ST2L was identified as an orphan receptor (Tominaga et al., FEBS Lett. 258:301-304, 1989) and a marker of Th2 cells involved in inflammatory processes, especially in the production of Th2-associated cytokines (Meisel et al., J. Immunol. 166:3143-3150; Trajkovic et al., Cytokine Growth Factor Rev. 15:87-95, 2004). The most characterized binding partner of ST2L is IL-33, which binds ST2L in conjunction with the IL-1R accessory protein (Schmitz et al., Immunity 23:479-490, 2005). ST2L signaling complex also includes a soluble receptor, sST2, which is produced by alternative splicing of ST2L, and can act as a negative regulator of ST2L signaling.
ST2L is selectively expressed on Th2 but not Th1 lymphocytes, mast cells, macrophages and eosinophils. ST2L signaling leads to generation of Th2 cytokines (IL-4, IL-5, IL-13), enhancement of Th2 effector functions, and proliferation of Th2 cells (Kakkar and Lee, Nature Reviews 7:827-840, 2008). Inhibition of ST2L activity attenuates Th2-dominated immune responses, such as lung eosinophilia, airway hyperresponsiveness, and arthritis in animal models (Coyle et al., J. Experimental Medicine 190:895-902, 1999; Hayakawa et al., J. Biol. Chem. 282:26369-26380, 2007; Leung et al., J. Immunol. 173:145-150, 2004). Further support for the role of ST2L signaling in human allergic diseases is supported by association of an ST2L promoter polymorphism that enhances ST2 gene expression with increased risk of developing atopic dermatitis (Shimizu et al., Hum. Mol. Genet. 14:2919-2927, 2005), and by IL-33-induced phenotype with production of IL-5 and IL-13, eosinophilia, increased serum IgE and IgA levels, lung epithelial cell hyperplasia and increased mucus production (Schmitz et al., Immunity 23:479-490, 2005). Thus, modulators of ST2L signaling, such as neutralizing anti-ST2L antibodies, may have a therapeutic benefit for Th2-mediated conditions as well as for inflammatory diseases such as asthma, allergy, and atopic dermatitis.
Predictive pharmacokinetic, safety and efficacy studies will be required before any ST2L modulator for human use can be brought to the market place. Such studies will involve both in vitro and in vivo testing in animal models of ST2L-associated pathologies. Lack of cross-reactivity of the modulators with ST2Ls across species can pose a challenge in these studies. Thus, use of, for example, antibody-based ST2L modulators may require evaluation of cross-reactivity of the antibodies between species, generation of surrogate antibodies against a ST2L polypeptide expressed by a particular model animal, as well as significant in vitro characterization of such surrogate antibodies. Evaluation of cross-reactivity, surrogate generation and in vitro characterization will require the use of ST2L polynucleotides and polypeptides from a suitable animal model. Importantly, the identification of suitable animal models for the above-mentioned studies requires the identification of animal species expressing ST2L with high identity and homology to human ST2L.
Thus, a need exists for the identification of polynucleotides encoding ST2L and ST2L polypeptides being expressed in an animal model identified as suitable for the predictive pharmacokinetic, safety and efficacy studies of ST2L modulators. A need also exists for related methods such as methods of expressing such polypeptides and testing the cross-reactivity of ST2L modulators.